1. Field of the Invention
The present invention relates to a biocatalytic method of preparing optically pure precursors of paroxetine, and more particularly, it relates to an improved method of resolving a first racemic precursor of paroxetine into a second, optically pure precursor of paroxetine. Additionally, the present invention relates to a method of preparing paroxetine, an optically pure compound, from a racemic precursor.
2. Description the Background Art
U.S. Pat. No. 4,007,196 and U.S. Pat. No. 4,902,801, both incorporated by reference herein, disclose compounds of formula I: ##STR1## in which R.sup.1 represents hydrogen, trifluoro (C.sub.1-4) alkyl, alkyl or alkynyl, R.sup.2 represents an alkyl or alkynyl group having 1-4 carbon atoms, or a phenyl group optionally substituted by C.sub.1-4 alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy groups. Alternately R.sup.2 may represent a tetrahydronaphthyl group. X represents hydrogen, an alkyl having 1-4 carbon atoms, or an alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio or aralkyloxy group.
The compounds of formula I have pharmacological properties that make them useful as anti-depressants. One compound that has proved especially valuable is the serotonin (5-HT) uptake inhibitor paroxetine [R.sup.1 .dbd.H, R.sup.2 =(1,3-benzodioxyl-5-yl), X.dbd.4-F], the pharmacologically active form of which is the (-)-trans isomer. The (-)-trans isomer (i.e., the active form) of paroxetine exhibits the (3S,4R) absolute stereoconfiguration according to Plenge et al. [J. Pharm. Pharmacol. 1987, 39: 877-882].
In U.S. Pat. No. 4,902,801 and U.S. Pat. No. 4,007,196, paroxetine is prepared from a (3S,4R)-trans precursor compound of formula (II): ##STR2## in which R is CH.sub.3 or H. The piperidine carbinol compounds of formula (II) are in turn prepared by reduction of a racemic trans ester precursor compound of formula (III): ##STR3## in which R is CH.sub.3 or H and R.sup.1 is CH.sub.3 or C.sub.2 H.sub.5. The reduction is carried out conventionally using a metal hydride, for example lithium aluminum hydride or aluminum hydride, in an inert solvent such as tetrahydrofuran or in a tetrahydrofuran/toluene mixture. Following reduction of the racemic trans ester precursor compound of formula (III), the precursor compounds of formula (II) are obtained in the trans configuration but as a mixture of (3R,4S) and (3S,4R) enantiomers. The precursor compounds of formula (II) are then resolved into their respective enantiomeric forms by conventional methods, such as diastereometric crystallization of salts with chiral acids such as, for example (+)-2'-nitrotartranilic acid or (-)-di-p-toluoyltartaric acid.
Paroxetine is prepared from the (3S,4R)-trans precursor compound of formula (II) making use of the procedures set out in U.S. Pat. No. 4,902,801 or U.S. Pat. No. 4,007,196.
This procedure has the disadvantage, however, that the diastereometric crystallization process is cumbersome and relatively expensive. Further, the reduction step, which is expensive, is performed prior to resolving the stereoisomers, thereby making it necessary to discard half of the expensive precursor compound of formula (II). In addition, since the carboxylate function is also reduced during the preparation of the precursor compound of formula (II), racemization and recycle of the (3R,4S) precursor compound of formula (II) is difficult.
Accordingly, there has been a need to prepare the precursor compound of formula (II) in a less cumbersome, less expensive manner.